Hypertrophic cardiomyopathy (HCM) is a an inherited heart disease with a prevalence of about 1 in 500 of the general population which results in severe thickness of the heart walls, particularly, of the left ventricle (LV). It has markedly variable clinical presentations, often causes disabling symptoms, and is probably the most common cause of sudden death in otherwise healthy young individuals such as athletes. A notable feature in HCM is the marked phenotypic heterogeneity. The severity and distribution of the left ventricular hypertrophy varies significantly. Other features include propensity to arrhythmias and sudden death, myocardial ischemia, LV systolic and diastolic dysfunction and intracavitary ventricular obstruction. HCM also demonstrates genetic heterogeneity, one of several genes and more than one mutation in a particular gene can cause HCM. HCM has been shown to be caused by mutations in 7 genes, cardiac beta myosin heavy chain on chromosome 14q11-12, alpha tropomyosin on chromosome 15q2, cardiac troponin-T on chronosome 1q3, cardiac myosin binding protein-C on chromosome 11p11.2, and the essential light chain of myosin (chromosome 3p) and regulatory light chains of myosin (chromosome 12q), cardiac troponin-T on chromosome 1, and troponin-I on chromosome 19. A locus in chromosome 7 has also been linked to HCM associated with Wolff-Parkinson-White syndrome. All the genes that have been identified to date encode for contractile (sarcomeric) proteins, However, these genes probably account for less than 50% of cases of HCM, and other non-sarcomeric genes may also cause HCM. Genotype-phenotype correlation studies have provided evidence that the clinical features in HCM are to some extent determined by the genotype. One clinical finding is that disease penetrance, that is the number of subjects with the mutation who develop the cardiac hypertrophy is mutation specific. For example, the disease penetrance is 100%in patients in whom HCM caused by Arg403Gln beta myosin mutation, that is all the children and adults with the mutation shown by filled symbols develop cardiac hypertrophy. The cardiac morphology is often quite distinct in HCM. In asymmetrical septal hypertrophy (ASH) the septum is predominantly hypertrophied. In the IHSS form of the disease there is obstruction to LV outflow caused by a narrowed LV outflow tract and anterior motion of a mitral valve leaflet. In the Japanese form of HCM the hypertrophy affects the apex of the heart. In a mid-cavity form of HCM the hypertrophy is mainly at the level of the papillary muscle. A narrow tunnel connects the proximal LV with a distal aneurysm. Mid-cavity HCM is strongly associated with essential and regulatory light chains of myosin and a myosin heavy chain mutation which interacts with the light chains. In one kindred in which HCM is caused by an ELC mutation, 6 family members had this rare form of HCM. The mechanism of sudden death also appears to be to some extent mutation-specific. In patients with the Arg403Gln mutation the cause of syncope and sudden death is often myocardial ischemia as shown by myocardial perfusion defects during exercise thallium scintigraphy, EKG changes during atrial pacing, and hypotension with onset of atrial pacing, mimicking a tachycardia. The myocardial ischemia may be reversed with verapamil and beta blocker therapy. Studies are being conducted to identify novel genetic causes of HCM and dilated cardiomyopathies, and to determine the natural history of determined mutations. Cardiac hypertrophy varies significantly in HCM, even in affected individuals with the same mutation. We are conducting a double-blind placebo-controlled study the enalapril (ACE inhibitor) and losartan (AT1 receptor inhibitor) to cause regression of LV hypertrophy and to improve myocardial perfusion and LV diastolic function in non-obstructive HCM. As an alternative to cardiac surgery, we have studied the ability of pacemaker therapy to improve severe drug-refractory symptoms and relieve LV outflow obstruction in patients in whom the LV hypertrophy results in intra-cavitary obstruction. The evidence indicates that the hemodynamic and symptomatic benefits of this novel therapy are maintained 5 years after pacemaker insertion. In many of the patients the reduction in LV outflow obstruction is maintained after six months of switching off of the pacemaker. This finding provides further evidence for cardiac adaptive changes and remodelling in response to prolonged pacing. Severity of obstructive hypertrophic cardiomyopathy (HCM) increases in children but there is no uniform opinion as to its management. Therapeutic options include pharmacotherapy, cardiac surgery and transplantation. This study investigates the ability of dual chamber (DDD) pacing to reduce intracavitary obstruction in HCM children during a period of rapid body growth. DDD pacing has been performed in 40 with obstructive HCM between the ages of 5 and 15 years (mean age, 11+/-4 years). Two sudden deaths have occurred during a mean follow up of 39+/-10 months: cumulative annual sudden death-rate of 1.9%. In addition, one child died following implatation of a defibrillator, and 3 patients underwent cardiac surgery. Therefore, DDD pacing has significantly reduced the LV obstruction and improved exercise performance in most of the children. Further studies are necessary to determine whether the symptomatic and hemodynamic benefits are maintained with further body growth. In another study, we examine in 44 patients the ability of a special pacemaker which autoregulates its programming to improve management of obstructive HCM by this novel therapy.